4-2812421-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001122681.2(SH3BP2):c.-4-8193A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0412 in 1,550,288 control chromosomes in the GnomAD database, including 3,199 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.091 (1350 hom., cov: 33)
  • Exomes 𝑓: 0.036 (1849 hom.)
• Consequence: SH3BP2 NM_001122681.2 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.10

Genes affected

SH3BP2 (HGNC:10825): (SH3 domain binding protein 2) The protein encoded by this gene has an N-terminal pleckstrin homology (PH) domain, an SH3-binding proline-rich region, and a C-terminal SH2 domain. The protein binds to the SH3 domains of several proteins including the ABL1 and SYK protein tyrosine kinases , and functions as a cytoplasmic adaptor protein to positively regulate transcriptional activity in T, natural killer (NK), and basophilic cells. Mutations in this gene result in cherubism. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2009]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 4-2812421-A-G is Benign according to our data. Variant chr4-2812421-A-G is described in ClinVar as [Benign]. Clinvar id is 1239506.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr4-2812421-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.24 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SH3BP2	NM_001122681.2	c.-4-8193A>G		intron_variant		ENST00000503393.8
SH3BP2	NM_001145855.2	c.24A>G	p.Thr8=	synonymous_variant	1/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SH3BP2	ENST00000503393.8	c.-4-8193A>G		intron_variant		1	NM_001122681.2	P2

Frequencies

GnomAD3 genomes AF: 0.0913 AC: 13888 AN: 152092 Hom.: 1343 Cov.: 33

Gnomad AFR AF: 0.244

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0781

Gnomad ASJ AF: 0.0424

Gnomad EAS AF: 0.0400

Gnomad SAS AF: 0.0245

Gnomad FIN AF: 0.0138

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0269

Gnomad OTH AF: 0.0695

GnomAD3 exomes AF: 0.0504 AC: 7552 AN: 149768 Hom.: 415 AF XY: 0.0449 AC XY: 3610 AN XY: 80414

Gnomad AFR exome AF: 0.247

Gnomad AMR exome AF: 0.0981

Gnomad ASJ exome AF: 0.0402

Gnomad EAS exome AF: 0.0396

Gnomad SAS exome AF: 0.0250

Gnomad FIN exome AF: 0.0135

Gnomad NFE exome AF: 0.0284

Gnomad OTH exome AF: 0.0455

GnomAD4 exome AF: 0.0358 AC: 50002 AN: 1398078 Hom.: 1849 Cov.: 31 AF XY: 0.0344 AC XY: 23713 AN XY: 689600

Gnomad4 AFR exome AF: 0.247

Gnomad4 AMR exome AF: 0.0945

Gnomad4 ASJ exome AF: 0.0397

Gnomad4 EAS exome AF: 0.0618

Gnomad4 SAS exome AF: 0.0247

Gnomad4 FIN exome AF: 0.0141

Gnomad4 NFE exome AF: 0.0281

Gnomad4 OTH exome AF: 0.0438

GnomAD4 genome AF: 0.0915 AC: 13925 AN: 152210 Hom.: 1350 Cov.: 33 AF XY: 0.0872 AC XY: 6490 AN XY: 74432

Gnomad4 AFR AF: 0.244

Gnomad4 AMR AF: 0.0785

Gnomad4 ASJ AF: 0.0424

Gnomad4 EAS AF: 0.0401

Gnomad4 SAS AF: 0.0243

Gnomad4 FIN AF: 0.0138

Gnomad4 NFE AF: 0.0269

Gnomad4 OTH AF: 0.0707

Alfa AF: 0.0566 Hom.: 286

Bravo AF: 0.103

Asia WGS AF: 0.0700 AC: 244 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 14, 2021

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
Cadd	Benign	0.83
Dann	Benign	0.74

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1709004; hg19: chr4-2814148; COSMIC: COSV67748357; COSMIC: COSV67748357;